Nuclear receptor CAR activation mechanism: What is unique about this system is the fact that therapeutics and xenobiotics do not directly bind to CAR to activate it. We previously determined that threonine 38 of CAR regulates this indirect activation through its phosphorylation and dephosphorylation Sci. Signal. 2013). Phosphorylation of Thr38 inactivates CAR and retains it in the cytoplasm. Drugs such as phenobarbital repress epidermal growth factor receptor (EGFR) signaling to stimulate dephosphorylation for CAR activation and nuclear translocation. Protein phosphatase 2A (PP2A) catalyzes this dephosphorylation utilizing the receptor for activated C-kinase1 (RACK1) as the regulatory subunit. In response to phenobarbital, phosphorylated CAR recruits PP2Ac/RACK1 for dephosphorylation and activation. Here we have now determined the homodimer-mediated mechanism by which CAR controls its phosphorylation in response to EGFR signaling and to phenobarbital. Phosphorylated CAR forms its homodimer that buries the PP2A/RACK1 binding site within the homodimer interface, preventing CAR from dephosphorylation and keeping CAR being inactivated. Phenobarbital indirectly and CAR ligands directly dissociate CAR homodimer, allowing PP2A/RACK1 to bind and dephosphorylate CAR for activation. CAR is found to require p38MAPK to bind to and activate its target genes. Once CAR binds and a promoter as a p38 complex, it is phosphorylated at threonine 38 by p38, thereby inactivated. Thus, p38 links CAR activation and inactivation in the nucleus. Conversely, CAR attenuates phosphorylation of p38 in mouse liver, which can be a cell signaling for hepatocellular carcinoma. Threonine 38 of CAR is conserved as a phosphorylation motif in the majority of human nuclear receptors. We examined serine 216 of estrogen receptor alpha that is phosphorylated in mouse immune cells such as neutrophils and brain microglia. Subsequently, we generated Knock-In mice (Esr1S216A) bearing non-phosphomimetic Ser216Ala mutation and found that phosphorylated ERalpha is an anti-inflammatory in microglia. Our study with 11 different nuclear receptors defined phosphorylation of the conserved motif as protein degradation signal of nuclear receptors. FXR was found to utilize this phosphorylation to link ligand activation, inactivation and degradation in the nucleus. Thus, the conserved phosphorylation motif within the DNA binding domain has provided a molecular basis for nuclear receptor regulations beyond CAR. Nuclear receptor PXR, functions and diseases: PXR is activated by drugs such as statins. We previously demonstrated that statin-activated PXR recruits protein phosphate 2C to dephosphorylate serine/threonine kinase 2 (SGK2). Phosphorylated SGK2, utilizing non-phosphorylated SGK2 as a co-regulator to activate gluconeogenic genes (Sci. Rep, 2014). This PXR-SGK2 signaling may contribute to side-effects caused by statin therapy, increasing blood glucose levels and risk to develop type 2 diabetes. We have now characterized that PXR is glucose-regulated signal transduction factor that regulate hepatic gluconeogenesis. PXR is phosphorylated at Ser350 in mouse liver during fasting. This phosphorylation is regulated by glucose. Vaccinia virus-related kinase 1 (VRK1) directly phosphorylates Ser350 in human liver cells cultured in low glucose media. Similar to statin-activated PXR, phosphorylated PXR scaffolds PP2C to dephosphorylate SGK2, activating gluconeogenic genes. Thus, it appears that PXR has originally eveloved as a signal transducer to maintain glucose homeostasis during fasting or starvation.